US10865210B2 - Synthesis of n-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines - Google Patents

Synthesis of n-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines Download PDF

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US10865210B2
US10865210B2 US16/230,381 US201816230381A US10865210B2 US 10865210 B2 US10865210 B2 US 10865210B2 US 201816230381 A US201816230381 A US 201816230381A US 10865210 B2 US10865210 B2 US 10865210B2
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pyrimidine
lactam
pyrrolo
alkyl
alkylthio
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US20190135820A1 (en
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Alexander Smith
Hannah S. White
Francis Xavier Tavares
Sergiy Krasutsky
Jian-Xie Chen
Roberta L. Dorrow
Hua Zhong
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Kelexsyn Inc
Pharma Advance Inc
G1 Therapeutics Inc
Curia Global Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems

Definitions

  • This invention is in the area of synthesizing pyrimidine-based compounds useful in the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
  • WO 2013/148748 (U.S. Ser. No. 61/617,657) entitled “Lactam Kinase Inhibitors” filed by Tavares, and also assigned to G1 Therapeutics likewise describes the synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines via the coupling reaction of a fused chloropyrimidine with a heteroaryl amine to form the central disubstituted amine.
  • WO 2013/163239 (U.S. Ser. No. 61/638,491) “Synthesis of Lactams” describes a method for the synthesis of this class of compounds with the variation that in the lactam preparation step, a carboxylic acid can be cyclized with a protected amine in the presence of a strong acid and a dehydrating agent, which can be together in one moiety as a strong acid anhydride.
  • the purported improvement is that cyclization can occur without losing the protecting group on the amine before cyclization.
  • the typical leaving group is “tBOC” (t-butoxycarbonyl).
  • the application teaches (page 2 of WO 2013/163239) that the strong acid is, for example, trifluoroacetic acid anhydride, tribromoacetic acid anhydride, trichloroacetic acid anhydride or mixed anhydrides.
  • An additional step may be necessary to take off the N-protecting group.
  • the dehydrating agent can be a carbodiimide-based compound such as DCC (N,N-dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, or DIC (N,N-diisopropylcarbodiimide).
  • DCC and DIC are in the same class of reagents-carbodiimides. DIC is sometimes considered better because it is a liquid at room temperature, which facilitates reactions.
  • WO 2015/061407 filed by Tavares and licensed to G1 Therapeutics also describes the synthesis of these compounds via the coupling of a fused chloropyrimidine with a heteroaryl amine to form the central disubstituted amine.
  • WO '407 focuses on the lactam production step and in particular describes that the fused lactams of these compounds can be prepared by treating the carboxylic acid with an acid and a dehydrating agent in a manner that a leaving group on the amine is not removed during the amide-forming ring closing step.
  • WO 2014/144326 filed by Strum et al. and assigned to G1 Therapeutics describes compounds and methods for protection of normal cells during chemotherapy using pyrimidine based CDK4/6 inhibitors.
  • WO 2014/144596 filed by Strum et al. and assigned to G1 Therapeutics describes compounds and methods for protection of hematopoietic stem and progenitor cells against ionizing radiation using pyrimidine based CDK4/6 inhibitors.
  • WO 2014/144847 filed by Strum et al. and assigned to G1 Therapeutics describes HSPC-sparing treatments of abnormal cellular proliferation using pyrimidine based CDK4/6 inhibitors.
  • WO2014/144740 filed by Strum et al.
  • WO 2015/161285 filed by Strum et al. and assigned to G1 Therapeutics describes tricyclic pyrimidine based CDK inhibitors for use in radioprotection.
  • WO 2015/161287 filed by Strum et al. and assigned to G1 Therapeutics describes analogous tricyclic pyrimidine based CDK inhibitors for the protection of cells during chemotherapy.
  • WO 2015/161283 filed by Strum et al. and assigned to G1 Therapeutics describes analogous tricyclic pyrimidine based CDK inhibitors for use in HSPC-sparing treatments of RB-positive abnormal cellular proliferation.
  • WO 2015/161288 filed by Strum et al. and assigned to G1 Therapeutics describes analogous tricyclic pyrimidine based CDK inhibitors for use as anti-neoplastic and anti-proliferative agents.
  • WO 2016/040858 filed by Strum et al. and assigned to G1 Therapeutics describes the use of combinations of pyrimidine based CDK4/6 inhibitors with other anti-neoplastic agents.
  • WO 2016/040848 filed by Strum et al. and assigned to G1 Therapeutics describes compounds and methods for treating certain Rb-negative cancers with CDK4/6 inhibitors and topoisomerase inhibitors.
  • WO 2007/061677 filed by Bell et al. describes aryl spirolactams as CGRP receptor antagonists wherein the lactam resides on the spiro ring.
  • WO 2008/073251 filed by Bell et al. describes constrained spirolactam compounds wherein the lactam resides on the spiro ring as CGRP receptor antagonists.
  • WO 2006/031606 filed by Bell et al. describes carboxamide spirolactam compounds wherein the spirolactam resides on the spiro ring as CGRP receptor antagonists.
  • 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidines are advantageously prepared by coupling an alkyl sulfone or alkyl sulfoxide substituted fused pyrimidine with a heteroaryl amine to form the central disubstituted amine in yields above about 50%.
  • the reaction is conducted at a temperature at or below about 20, 18, 16, 14, 12, or 10° C.
  • the ratio of amine to sulfone is at least about 2 to 1.
  • the ratio of amine to sulfone is at least about 3 to 1.
  • Using an alkyl sulfone or alkyl sulfoxide substituted fused pyrimidine instead of a chloro substituted fused pyrimidine increases the yield of the coupled diamine product.
  • a new process is provided for the preparation of a 2′-(alkylsulfonyl or alkylsulfinyl)-pyrrolo[2,3-d]pyrimidines that can be used in the coupling reaction with the heteroaryl amine.
  • the invention provides the 2′-(alkylsulfonyl or alkylsulfinyl)-pyrrolo[2,3-d]pyrimidine is of the following structure.
  • the 2′-(alkylsulfonyl or alkylsulfinyl)-pyrrolo[2,3-d]pyrimidine is prepared using either an ester or an aldehyde starting material.
  • the ester may be an alkyl 4-chloro-2-(alkylthio)pyrimidine-5-carboxylate, such as ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate.
  • the aldehyde may be a 4-chloro-2-(alkylthio)pyrimidine-5-carbaldehyde, such as 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde.
  • reaction from the ester to the key intermediate 2′-(alkylsulfonyl or alkylsulfinyl)-pyrrolo[2,3-d]pyrimidine typically takes seven steps (some of which can be telescoped without compound isolation), each of which typically provide yields of greater than 50%. Each step is described in detail below.
  • the process for the preparation of the 2′-(alkylsulfonyl or alkylsulfinyl)-pyrrolo[2,3-d]pyrimidine is a facile and efficient route that consists of seven steps with only five isolations, all by crystallization. No column chromatography is required, which allows the process to be scalable for large manufacturing batches. Further, the process work-up conditions can successfully purge the majority of the palladium after Step 5. The level of residual palladium observed is below the ppm residual threshold for heavy metal content.
  • the invention includes new intermediates of Formula II that can be used in the process of preparing lactam-pyrrolo[2,3-d]pyrimidines of Formula IV.
  • the synthesis of compounds of Formula I, Formula II, Formula III, and Formula IV is provided.
  • compounds of Formula I, Formula II, and Formula III are synthetic precursors to Formula IV.
  • R 1 is selected from: alkyl, aryl, haloalkyl, and arylalkyl;
  • R 2 and R 3 are independently selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl;
  • R 4 is selected from: hydrogen, silyl, haloalkyl, —C(O)alkyl, —S(O) 2 alkyl, —S(O) 2 haloalkyl, —S(O) 2 aryl, and —S(O) 2 arylalkyl; and
  • R 5 is selected from: hydrogen, halogen, —N(alkyl)(alkoxy), —NCH 3 OMe, alkoxy, aryloxy, —OCH 2 aryl, —OC(O)alkyl, —OC(O)aryl, and —OC(O)arylalkyl.
  • the heteroaryl amine is dissolved in a polar solvent, and the alkyl sulfone or alkyl sulfoxide is added portionwise at temperatures at or below about 20, 18, 16, 14, 12, or 10° C., wherein, a ratio of amine to sulfone of at least about 2 to 1 and a ratio of base to sulfone of at least 2 to 1 is used to afford the central disubstituted amine in yields above about 50%.
  • the heteroaryl amine is dissolved in a polar solvent, and the alkyl sulfone or alkyl sulfoxide is added portionwise wherein, a ratio of amine to sulfone of at least about 2 to 1 and a ratio of base to sulfone of at least 2 to 1 is used to afford the central disubstituted amine in yields above about 50%.
  • the heteroaryl amine is dissolved in a polar solvent, and the alkyl sulfone or alkyl sulfoxide is added portionwise at temperatures at or below about 20, 18, 16, 14, 12, or 10° C., wherein, a ratio of amine to sulfone of at least about 3 to 1 and a ratio of base to sulfone of at least 2 to 1 is used to afford the central disubstituted amine in yields above about 50%.
  • the heteroaryl amine is dissolved in a polar solvent, and the alkyl sulfone or alkyl sulfoxide is added portionwise at temperatures at or below about 20, 18, 16, 14, 12, or 10° C., wherein, a ratio of amine to sulfone of at least about 3 to 1 and a ratio of base to sulfone of at least 3 to 1 is used. After complete addition the reaction mixture is quenched with ammonium chloride to recover the central disubstituted amine in yields above about 50%.
  • reaction mixture is quenched with ammonium chloride to recover the central disubstituted amine in yields above about 50%.
  • the base is LiHMDS.
  • a 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidine is prepared from an ester starting material and includes the following steps:
  • the oxidation, protection or deprotection above are reordered or removed as allowed by the reagents and substrates being used. For example, if the lactam amine of step (i) above is already protected then step (ii) is omitted.
  • step (vi) and step (vii) are switched.
  • the process to synthesize a compound of Formula IV includes the following steps:
  • the process to synthesize a compound of Formula IV includes the following steps:
  • the process to synthesize a compound of Formula IV includes the following steps:
  • the process to synthesize a 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidine from an aldehyde starting material includes the following steps:
  • the oxidation, protection, or deprotection above are reordered or removed as allowed by the reagents and substrates being used. For example, if the lactam amine of step (i) above is already protected then step (ii) is omitted.
  • step (iv) and step (v) are switched.
  • the process to synthesize a compound of Formula IV includes the following steps:
  • the process to synthesize a compound of Formula III includes the following steps:
  • the process to synthesize a compound of Formula II includes the following steps:
  • the process to synthesize a compound of Formula II includes the following steps:
  • the process to synthesize a compound of Formula I includes the following steps:
  • the process to synthesize a compound of Formula I includes the following steps:
  • Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;
  • R 2 is independently selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl;
  • each R 6 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 6 's on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
  • y is 0, 1, 2, 3 or 4;
  • R 12 is selected from:
  • Y is NH, O, S, or NR 14 ;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are independently N or CR 13 , wherein at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is CR 13 ;
  • R 13 is selected independently at each instance from: R 11 and R 7 , wherein one R 13 is R 7 ;
  • R 14 is selected from: —C(O)H, —C(O)alkyl, —C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R 7 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 8 R 9 , -(alkylene) m -C(O)—NR 8 R 9 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 10 , -(alkylene) m -S(O) n —R 10 , or -(alkylene) m -S(O) n —NR 8 R 9 any of which may be optionally R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0 or 1 and n is 0, 1 or 2;
  • R 8 and R 9 at each occurrence are independently:
  • R 10 and R 10 * at each occurrence is:
  • R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 10 , -(alkylene) m -O-alkylene-OR 10 , -(alkylene) m -S(O) n —R 10 , -(alkylene) m -NR 8 R 9 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 10 , -(alkylene) m -C(S)—R 10 , -(alkylene) m -C(O)—OR 10
  • R 11 is selected independently at each instance from: hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl.
  • Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;
  • R 2 is independently selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl;
  • each R 6 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 6 's on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
  • y is 0, 1, 2, 3 or 4;
  • R 12 is selected from:
  • Y is NH, O, S, or NR 14 ;
  • X 1 , X 2 , X 3 , and X 4 are independently N or CR 13 , wherein at least one of X 1 , X 2 , X 3 , and X 4 , is CR 13 ;
  • R 13 is selected independently at each instance from: R 11 and R 7 , wherein one R 13 is R 7 ;
  • R 14 is selected from: —C(O)H, —C(O)alkyl, —C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;
  • R 7 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 8 R 9 , -(alkylene) m -C(O)—NR 8 R 9 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 10 , -(alkylene) m -S(O) n —R 10 , or -(alkylene) m -S(O) n —NR 8 R 9 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;
  • R 8 and R 9 at each occurrence are independently:
  • R 10 is:
  • R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl,
  • n 0, 1, or 2;
  • n 0 or 1
  • R 11 is selected independently at each instance from: hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl.
  • R 12 is selected from:
  • R 12 is selected from:
  • R 12 is
  • R 12 is
  • the present invention thus includes at least the following features:
  • FIG. 1 illustrates the synthesis of Intermediate 1K from benzyl (1-(aminomethyl)cyclohexyl)carbamate.
  • benzyl (1-(aminomethyl)cyclohexyl)carbamate is Boc-protected.
  • nucleophilic attack by the Boc-protected species on 5-bromo-2,4-dichloropyrimidine affords selective displacement of chloride to afford a dihalo species.
  • the dihalo species is coupled selectively to displace bromide and afford an internal alkynyl species.
  • internal alkynyl species is cyclized to a 6-5 heteroaryl species.
  • Steps 7-9 the 6-5 heteroaryl species is further cyclized to afford Intermediate 1K.
  • FIG. 2 illustrates the SNAr coupling of Intermediate 1K to an appropriately substituted anilino species to afford a CDK inhibitor.
  • FIG. 3 illustrates the progressive decrease of Palladium levels measured in parts per million from compound 10 to 11 to 19 to the salt of 19. The final concentration of palladium is 1.47%. See example 3.
  • FIG. 4 is Formula I, Formula II, Formula III, and Formula IV.
  • the compounds in any of the Formulas described herein include racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers; such as rotamers, as if each is specifically described.
  • the present invention includes compounds of Formula II with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 CI, and 125 I respectively.
  • isotopically labelled compounds can be used in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
  • isotopes of carbon e.g., 13 C and 14 C, may be used.
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.
  • the substitution of a hydrogen atom for a deuterium atom can be provided in any of A, C, L or B. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within an R group selected from any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 *, R 9 , R 9 *, R 10 , R 10 *, R 11 , R 12 , R 13 , R 14 , and R x .
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH 2 , CD 2 H, CD 3 , CH 2 CD 3 , CD 2 CD 3 , CHDCH 2 D, CH 2 CD 3 , CHDCHD 2 , OCDH 2 , OCD 2 H, or OCD 3 etc.).
  • the unsubstituted carbons may be deuterated when two substituents are combined to form a cycle.
  • the compound of the present invention may form a solvate with solvents (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound.
  • solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound of the invention and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • a solvate can be in a liquid or solid form.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • —(C ⁇ O)NH 2 is attached through carbon of the keto (C ⁇ O) group.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C 1 -C 2 , C 1 -C 3 , or C 1 -C 6 .
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • C 1 -C 6 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C 1 -C 4 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.
  • the alkyl group is optionally substituted.
  • cycloalkyl or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context.
  • alkyl, alkoxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context.
  • Alkoxy is an alkyl group as defined above covalently bound through an oxygen bridge (—O—).
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • an “alkylthio” or a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (—S—).
  • the alkoxy group is optionally substituted as described above.
  • the thioalkyl group is optionally substituted as described above.
  • Amino is —NH 2 .
  • “Amide” or “carboxamide” is —C(O)NR a R b wherein R a and R b are each independently selected from hydrogen, alkyl, for example, C 1 -C 6 alkyl, alkenyl, for example, C 2 -C 6 alkenyl, alkynyl, for example, C 2 -C 6 alkynyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C 0 -C 4 alkyl(C 3 -C 7 heterocycloalkyl), —C 0 -C 4 alkyl(aryl), and —C 0 -C 4 alkyl(heteroaryl); or together with the nitrogen to which they are bonded, R a and R b can form a C 3 -C 7 heterocyclic ring.
  • the R a and R b groups are each independently optionally substituted as described above.
  • carbocyclyl As used herein, “carbocyclyl”, “carbocyclic”, “carbocycle” or “cycloalkyl” is a saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms and from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
  • a carbocyclyl group has 3 to 9 ring carbon atoms (“C 3-9 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 5 ), cyclooctenyl (C 5 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), and the like.
  • the carbocyclyl group can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more heterocyclyl, aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of carbocycle is optionally substituted with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • Haloalkyl indicates both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.
  • Haloalkoxy indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • Halo or “halogen” indicates independently any of fluoro, chloro, bromo or iodo.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • the one or more fused carbocyclyl or heterocyclyl groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl groups that optionally contain 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4-methylenedioxyphenyl group.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described above.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • Arylalkyl is an aryl group as defined herein attached through an alkyl group.
  • Non-limiting examples of arylalkyl groups include:
  • Aryloxy is an aryl group as defined herein attached through a —O— linker.
  • Non-limiting examples of aryloxy groups include:
  • Alkylsulfinyl and “alkyl sulfoxide” as defined herein are represented by
  • Alkylsulfonyl and “alkyl sulfone” as defined herein are represented by
  • 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidines are advantageously prepared by coupling an alkyl sulfone or alkyl sulfoxide substituted fused pyrimidine with a heteroaryl amine to form the central disubstituted amine.
  • Using an alkyl sulfone or alkyl sulfoxide substituted fused pyrimidine instead of a chloro substituted fused pyrimidine increases the yield of the coupled diamine product and decreases the required temperature, resulting in fewer side products and thus impurities.
  • the coupling can occur in a polar aprotic solvent at a reduced temperature if desired in the presence of a base that facilitates the reaction.
  • the coupling can be achieved by adding a sulfone to a stirred solution of heteroaryl amine in THF at room temperature or lower, in the presence of LiHMDS.
  • the amine is preferably added last to reduce the occurrence of dimerization side reactions.
  • the pyrimidine is fused to a pyrrole/spirocyclic lactam ring system.
  • the sulfone can be 2′-(methylsulfonyl)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one or a derivative thereof.
  • the pyrimidine is fused to a pyrrole/cyclic lactam system.
  • the sulfone can be 2-(methylsulfonyl)-8,9-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin-6(7H)-one or a derivative thereof.
  • Step 1 Method to Couple Heteroaryl Amines to Sulfones/Sulfoxides
  • Step 1 a heteroaryl amine is reacted with an 2′-(alkylsulfonyl)-lactam-pyrrolo[2,3-d]pyrimidine or 2′-(alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidine in the presence of a base to afford a 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the heteroaryl amine is mixed with an appropriate base in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in.
  • the 2′-(alkylsulfonyl)-lactam-pyrrolo[2,3-d]pyrimidine or 2′-(alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidine is then added as one or more additions. Any molar ratio of the two reactants can be used that achieves the desired results. Typically an excess of the heteroaryl amine is useful, for example about 3 equiv. of heteroaryl amine to about 1.0 equiv. of sulfone or sulfoxide.
  • the reaction can be carried out at any temperature that allows the reaction to take place. It has been found that the reaction can be conducted at below room temperature.
  • reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the heteroaryl amine is 5-(4-methylpiperazin-1-yl)pyridin-2-amine
  • the 2′-(alkylsulfonyl)-lactam-pyrrolo[2,3-d]pyrimidine is 2′-(methylsulfonyl)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one
  • the base is LiHMDS
  • the solvent is THF
  • the temperature is about 5° C.
  • the time is about one hour.
  • the base used in Step 1 can be any suitable base, including but not limited to LiHMDS, NaHMDS, NaH, KH, LDA, DIPEA (N,N-diisopropylethylamine), DMAP (4-Dimethylaminopyridine), DBU (1,8 Diazabicycloundec-7-ene), TEA (Triethylamine), pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO (1,4-diazabicyclo[2.2.2]octane), 1,5-diazabicyclo[4.3.0]non-5-
  • the solvent used in Step 1 can be any suitable organic solvent, including but not limited to DMAc (N,N-dimethylacetamide), DCM (Dichloromethane), THF (Tetrahydrofuran), DMF (N,N-dimethylformamide), ACN (Acetonitrile), DMAP (4-Dimethylaminopyridine), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME (Dimethoxyethane), DMSO (Dimethylsulfoxide), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA (Hexamethylphosphoramide), methanol, MTBE (Methyl Tertiary Butyl Et
  • the solvent used in Step 1 is dioxane.
  • the solvent is selected from DCM, EtOAc, ethanol, dioxane, tert-butyl alcohol, and THF.
  • the temperature used in Step 1 can be, for example, from about 20 to about 25° C., about 15 to about 30° C., about 10 to about 35° C., about 5 to about 40° C., or from about 0 to about 50° C. In one non-limiting embodiment, the temperature is maintained at or below room temperature. Alternatively, while less typical, the reaction can be carried out at elevated temperatures.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 1 for about 10 minutes to about 10 hours, about 30 minutes to about 5 hours, about 45 minutes to about 3 hours, or about 1 to about 2 hours.
  • the crude reaction mixture is quenched with water. In another embodiment the crude reaction mixture is quenched with saturated ammonium chloride.
  • the sulfone is added portionwise with at least about 5, 10, 15, or 20 minute stirring intervals. In one embodiment the sulfone is added portionwise with an at least 10 minute stirring interval.
  • the 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine is used as a free base.
  • the 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine is converted to a salt (for example Step 2).
  • the 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine is a compound of Formula X.
  • WO 2013/163239 and WO 2015/061407 describe the coupling of a heteroaryl amine to a lactam-pyrrolo[2,3-d]pyrimidine through a leaving group selected from Cl, Br, I, —S-Me, —S-aryl, —S-heteroaryl, SOMe, SO 2 Me, SOalkyl, SO 2 alkyl, SOcycloalkyl, SO 2 cycloalkyl, SOaryl, SO 2 aryl, hydroxy, hydroxyalkyl, hydroxyaryl, and hydroxyheteroaryl.
  • a leaving group selected from Cl, Br, I, —S-Me, —S-aryl, —S-heteroaryl, SOMe, SO 2 Me, SOalkyl, SO 2 alkyl, SOcycloalkyl, SO 2 cycloalkyl, SOaryl, SO 2 aryl, hydroxy, hydroxyalkyl, hydroxyaryl, and hydroxyheteroary
  • Step 2 Method to Form Salt of 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine
  • Step 2 a 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine is reacted with an acid to afford a 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine salt.
  • the 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine is mixed with an appropriate acid in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in.
  • the solvent is an acid.
  • an anti-solvent can be used. Any molar ratio of the two reactants can be used that achieves the desired results. Typically an excess of the acid is useful.
  • the reaction can be carried out at any temperature that allows the reaction to take place. It has been found that the reaction can be conducted at room temperature. The reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 2′-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidine salt.
  • the acid is HCl.
  • the solvent used in Step 2 can be any suitable organic solvent, including but not limited to DMAc (N,N-dimethylacetamide), DCM (Dichloromethane), THF (Tetrahydrofuran), DMF (N,N-dimethylformamide), ACN (Acetonitrile), DMAP (4-Dimethylaminopyridine), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME (Dimethoxyethane), DMSO (Dimethylsulfoxide), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA (Hexamethylphosphoramide), methanol, MTBE (Methyl Tertiary Butyl Et
  • the solvent is about 6M aqueous HCl. In another embodiment the solvent is about 4M HCl in dioxane. In another embodiment the solvent is a mixture of solvents. In one embodiment the mixture of solvents is a mixture of DCM and methanol.
  • the solvent is about 2M aqueous HCl. In another additional embodiment the solvent is 2M aqueous HCl.
  • the anti-solvent used in Step 2 can be any suitable organic solvent, including but not limited to DMAc (N,N-dimethylacetamide), DCM (Dichloromethane), THF (Tetrahydrofuran), DMF (N,N-dimethylformamide), ACN (Acetonitrile), DMAP (4-Dimethylaminopyridine), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME (Dimethoxyethane), DMSO (Dimethylsulfoxide), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA (Hexamethylphosphoramide), methanol, MTBE (Methyl Tertiary But
  • the temperature used in Step 2 can be, for example, from about 20 to about 25° C., about 15 to about 30° C., about 10 to about 35° C., about 5 to about 40° C., about 0 to about 50° C., or from about 0 to about 70° C.
  • the temperature is maintained at or below room temperature.
  • the reaction can be carried out at elevated temperatures.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 2 for about 10 minutes to about 10 hours, about 30 minutes to about 5 hours, about 45 minutes to about 3 hours, or about 1 to about 2 hours.
  • the salt is a di-HCl salt.
  • the 2′-(alkylsulfonyl)-lactam-pyrrolo[2,3-d]pyrimidine is a spirocycle, for example, 2′-(methylsulfonyl)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one.
  • Step 1 an alkyl 4-halo-2-(alkylthio)pyrimidine-5-carboxylate is reacted with a lactam amine in nucleophilic substitution reaction to afford an alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate.
  • the alkyl 4-halo-2-(alkylthio)pyrimidine-5-carboxylate and lactam amine are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in along with a base that will facilitate the nucleophilic substitution reaction. Any molar ratio of the two reactants can be used that achieves the desired results.
  • a small molar excess of the lactam amine is useful, for example about 1.1 equiv. of lactam amine to about 1.0 equiv. of carboxylate.
  • the reaction can be carried out at any temperature that allows the reaction to take place. It has been found that the reaction can be facilitated with heat, including up to reflux. The reaction is allowed sufficient time to provide the desired yield, after which the batch is optionally cooled and purified by any suitable means, including filtration, crystallization, and column chromatography, to afford an alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate.
  • the alkyl 4-halo-2-(alkylthio)pyrimidine-5-carboxylate is ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate
  • the lactam amine is a spirolactam
  • the base is DIPEA
  • the solvent is DMAc
  • the temperature is about 95° C.
  • the time is about 60 hours.
  • the base used in Step 1 can be any suitable organic base, including but not limited to DIPEA (N,N-diisopropylethylamine), DMAP (4-Dimethylaminopyridine), DBU (1,8 Diazabicycloundec-7-ene), TEA (Triethylamine), pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO (1,4-diazabicyclo[2.2.2]octane), 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, pipe
  • the solvent used in Step 1 can be any suitable organic solvent, including but not limited to DMAc (N,N-dimethylacetamide), DCM (Dichloromethane). THF (Tetrahydrofuran), DMF (N,N-dimethylformamide), TFA (Trifluoroacetic acid), ACN (Acetonitrile), DMAP (4-Dimethylaminopyridine), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME (Dimethoxyethane), DMSO (Dimethylsulfoxide), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA (Hexamethylphosphoramide), methanol, MTBE (Met
  • the solvent used in Step 1 is dioxane.
  • the solvent is selected from DCM, EtOAc, ethanol, dioxane, tert-butyl alcohol, and THF.
  • the temperature used in Step 1 can be, for example, from about 50 to about 150° C., about 60 to about 125° C., about 70 to about 110° C., about 80 to about 100° C., or from about 90 to about 100° C. In one non-limiting embodiment, the temperature is selected from about 80 to about 100° C. In an alternative embodiment, the reaction temperature is higher than the solvent reflux by use of a reaction vessel that can maintain elevated pressures. Alternatively, while less typical, the reaction can be carried out at room temperature or below.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 1 for about 5 to about 110 hours, about 15 to about 100 hours, about 25 to about 90 hours, about 35 to about 80 hours, or about 50 to about 70 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield.
  • Step 2 an alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is reacted with a protecting group reagent to afford a protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate.
  • the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate and protecting group reagent are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in along with a base that will facilitate the installation of the protecting group. Any molar ratio of the two reactants can be used that achieves the desired results.
  • a small molar excess of the protecting group reagent is useful, for example about 1.5 equiv. of protecting group reagent to about 1.0 equiv. of alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate.
  • the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is ethyl 2-(methylthio)-4-(3-oxo-1,4-diazaspiro[5.5]undecan-1-yl)pyrimidine-5-carboxylate
  • the protecting group reagent is Boc-anhydride
  • the base is DMAP
  • the solvent is dichloromethane
  • the temperature is about 25° C.
  • the time is about 3 hours.
  • the initial lactam amine used was already protected.
  • the lactam substituted pyrimidine reacts appropriately without needing a protecting group.
  • the protecting group reagent used in Step 2 can be any suitable reagent that allows installation of any suitable protecting group, including but not limited to Boc-anhydride (tert-butyloxycarbonyl anhydride), Boc-Cl, CBz-Cl, (Carboxybenzyl chloride) methyl chloroformate, benzyl chloride, benzoyl chloride, allylic chloride, triflic anhydride, Tf-Cl, tosyl anhydride, and Ts-Cl.
  • the protecting group is Boc and the suitable reagent is either Boc-anhydride or Boc-Cl.
  • the protecting group is CBz and the suitable reagent is CBz-Cl.
  • the base used in Step 2 can be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, and Trizma.
  • DIPEA
  • the solvent used in Step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, water, and THF.
  • a mixture of solvents is used in Step 2.
  • the temperature used in Step 2 can be, for example, from about ⁇ 20° C. to about 100° C., about ⁇ 10° C. to about 80° C., about 0° C. to about 60° C., about 10° C. to about 40° C., or from about 20° C. to about 30° C. In one non-limiting embodiment, the temperature is selected from about 20° C. to about 30° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 2 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 4 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 3 Preparation of 5′-hydroxy-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine
  • Step 3 a protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is reacted with a base in an intramolecular cyclization to afford a 5′-hydroxy-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate and base are mixed in a suitable solvent, typically a neutral organic solvent that both the reactant and reagent dissolve in. Any molar ratio of the reactant and reagent can be used that achieves the desired results.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 5′-hydroxy-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is tert-butyl 1-(5-(ethoxycarbonyl)-2-(methyl thio)pyrimidin-4-yl)-3-oxo-1,4-diazaspiro[5.5]undecane-4-carboxylate, the base is DBU, the solvent is THF, the temperature is about 5° C., and the time is about 2 hours.
  • the base used in Step 3 can be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, or Trizma.
  • DIPEA
  • the solvent used in Step 3 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, water, and THF.
  • a mixture of solvents is used in Step 3.
  • the temperature used in Step 3 can be, for example, from about ⁇ 50° C. to about 50° C., about ⁇ 35° C. to about 40° C., about ⁇ 10° C. to about 30° C., about ⁇ 5° C. to about 20° C., or from about 0° C. to about 10° C. In one non-limiting embodiment, the temperature is selected from about 0° C. to about 10° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 3 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 4 Preparation of 5′-leaving Group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine
  • Step 4 a 5′-hydroxy-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is reacted with a leaving group reagent to afford a 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 5′-hydroxy-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and leaving group reagent are mixed in a suitable solvent, typically a neutral organic solvent that both the reactants dissolve in along with a base that will facilitate the reaction. Any molar ratio of the reactants can be used that achieves the desired results.
  • a small molar excess of the protecting group reagent is useful, for example about 1.6 equiv. of leaving group reagent to about 1.0 equiv. of 5′-hydroxy-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 5′-hydroxy-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is tert-butyl 5′-hydroxy-2′-(methylthio)-6′-oxo-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-7′(8′H)-carboxylate
  • the leaving group reagent is triflic anhydride
  • the base is TEA
  • the solvent is DCM
  • the temperature is about 0° C.
  • the time is about 3 hours.
  • the leaving group reagent used in Step 4 can be any suitable reagent that allows conversion of the hydroxyl group to any suitable leaving group, including but not limited to triflic anhydride, Tf-Cl, tosyl anhydride, and Ts-Cl.
  • the protecting group is triflate and the suitable reagent is either triflic anhydride or Tf-Cl.
  • the base used in Step 4 can be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, or Trizma.
  • DIPEA
  • the solvent used in Step 4 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • suitable organic solvent including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzen
  • the solvent is selected from DCM, diethyl ether, and THF.
  • a mixture of solvents is used in Step 4.
  • the solvent or mixture of solvents is aprotic so as to avoid reaction with the leaving group reagent.
  • the temperature used in Step 4 can be, for example, from about ⁇ 50° C. to about 50° C., about ⁇ 35° C. to about 35° C., about ⁇ 25° C. to about 25° C., about ⁇ 15° C. to about 15° C., or from about ⁇ 5° C. to about 5° C. In one non-limiting embodiment, the temperature is selected from about ⁇ 5° C. to about 5° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 4 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 4 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 5 a 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is reacted with a leaving group cleaving reagent to remove the leaving group and afford a 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and leaving group cleaving reagent are mixed in a suitable solvent, typically a neutral organic solvent that both the reactants dissolve in along with a catalyst that will facilitate the reaction. Any molar ratio of the reactants can be used that achieves the desired results.
  • a molar excess of the leaving group cleaving reagent is useful, for example about 2.0 equiv. of leaving group cleaving reagent to about 1.0 equiv. of 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is tert-butyl 2′-(methylthio)-6′-oxo-5′-(((trifluoromethyl)sulfonyl)oxy)-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-7′(8′H)-carboxylate
  • the leaving group cleaving reagent is triethylsilane
  • the catalyst is palladium tetrakis
  • the solvent is DMF
  • the temperature is about 50° C.
  • the time is about 14 hours.
  • the leaving group cleaving reagent used in Step 5 can be any suitable reagent that allows removal of the leaving group, including but not limited to trialkylsilanes.
  • the leaving group cleaving reagent is triethylsilane.
  • the catalyst used in Step 5 can be any suitable organometallic catalyst, including but not limited to Pd/C, palladium tetrakis, palladium acetate, [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II), Tris(dibenzylideneacetone)dipalladium(0), and allylpalladium(II) chloride.
  • organometallic catalyst including but not limited to Pd/C, palladium tetrakis, palladium acetate, [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II), Tris(dibenzylideneacetone)dipalladium(0), and allylpalladium(II) chloride.
  • multiple catalysts or a catalyst and cocatalyst are used in Step 5.
  • the solvent used in Step 5 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • suitable organic solvent including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzen
  • the solvent is selected from DMF, DMSO, ACN, and NMP.
  • a mixture of solvents is used in Step 5.
  • the solvent or mixture of solvents is aprotic so as to avoid reaction with the reagent.
  • the temperature used in Step 5 can be, for example, from about 0° C. to about 100° C., about 15° C. to about 85° C., about 25° C. to about 75° C., about 35° C. to about 65° C., or from about 45° C. to about 55° C. In one non-limiting embodiment, the temperature is selected from about 45° C. to about 55° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 5 for about 1 to about 30 hours, about 3 to about 25 hours, about 6 to about 20 hours, about 9 to about 16 hours, or about 12 to about 15 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively, if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 6 a 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is deprotected to afford a deprotected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and deprotecting reagent are mixed in a suitable solvent, typically an organic solvent that both reactants dissolve in. Any molar ratio of the reactant and deprotecting reagent can be used that achieves the desired results. Typically a large molar excess of the deprotecting reagent is useful, for example about 5 equiv.
  • deprotecting reagent to about 1.0 equiv. of 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a deprotected 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is tert-butyl 2′-(methylthio)-6′-oxo-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-7′(8′H)-carboxylate
  • the deprotecting reagent is TFA
  • the solvent is dichloromethane
  • the temperature is about 25° C.
  • the time is about 2 hours.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine was already deprotected because it was suitable for the prior reactions in the absence of a protecting group.
  • the protecting group is left on to be removed at a later step.
  • the deprotecting reagent used in Step 6 can be any suitable reagent that allows deprotection of any suitable protecting group, including but not limited to TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, formic acid, lactic acid, malic acid, malonic acid, methane sulfonic acid, oxalic acid, phthalic acid, salicyclic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, periodic acid, phosphinic acid, phosphoric acid, palladium on carbon with or without hydrogen gas, platinum on carbon with our without hydrogen gas, triethylsilane
  • the deprotecting reagent used in Step 6 is a basic deprotecting reagent, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine
  • the deprotecting reagent used in Step 6 is NaOMe.
  • the deprotection uses MeOH as a solvent with NaOMe as a base.
  • the reaction is heated for about 1, 2, 3, 4, 5, 6, 7, or 8 hours.
  • the reaction is cooled below room temperature before isolation.
  • the reaction is refluxed for about 3 hours, cooled to about 0° C., isolated, and washed with MeOH.
  • the solvent used in Step 6 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from TFA, DCM, THF, and chloroform.
  • a mixture of solvents is used in Step 6.
  • the deprotecting rea is selected from TFA, DCM, T
  • the temperature used in Step 6 can be, for example, from about ⁇ 20° C. to about 100° C., about ⁇ 10° C. to about 80° C., about 0° C. to about 60° C., about 10° C. to about 40° C., or from about 20° C. to about 30° C. In one non-limiting embodiment, the temperature is selected from about 20° C. to about 30° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 6 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 7 Optional Oxidation of 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine
  • Step 7 a 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is reacted with an oxidant to afford an 2′-(alkyl sulfonyl)-lactam-pyrrolo[2,3-d]pyrimidine or 2′-(alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and oxidant are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve. Any molar ratio of the reactant and oxidant can be used that achieves the desired results.
  • a large molar excess of the oxidant is useful, for example about 5 equiv. of oxidant to about 1.0 equiv. of 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford either a 2′-(alkylsulfonyl)-lactam-pyrrolo[2,3-d]pyrimidine or 2′-(alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is 2′-(methylthio)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one
  • the oxidant is oxone
  • the solvent is a mixture of water and acetonitrile
  • the temperature is about 25° C.
  • the time is about 2 hours.
  • the oxidant used in Step 7 can be any suitable reagent that allows oxidation to either the sulfone or sulfoxide oxidation state, including but not limited to oxone, hydrogen peroxide, mCPBA, sodium hypochlorite, and sodium chlorite.
  • the product is a sulfone and the oxidant is oxone.
  • the oxidant used is catalyzed with an additive.
  • the additive is Na 2 WO 4 .
  • the additive is Na 2 WO 4 and the oxidant is hydrogen peroxide.
  • the additive is Na 2 WO 4 and the oxidant is hydrogen peroxide and the reaction is conducted in a mixture of H 2 O and EtOH with heat.
  • the additive is Na 2 WO 4 and the oxidant is hydrogen peroxide and the reaction is conducted in a mixture of H 2 O and EtOH at about 60° C. for about 1, 2, 3, 4, 5, 6, 7, 8, or 9 hours.
  • the oxidant is added slowly to the reaction mixture. In one embodiment the oxidant is added over the course of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 minutes. In one embodiment the oxidant is added over the course of about 50 minutes. In one embodiment the addition over the course of 50 minutes results in a higher yield than a faster addition such as one over the course of 10 minutes.
  • the solvent used in Step 7 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from ACN, water, and dioxane.
  • a mixture of solvents is used in Step 7, for example, water and ACN.
  • the temperature used in Step 7 can be, for example, from about ⁇ 20° C. to about 100° C., about ⁇ 10° C. to about 80° C., about 0° C. to about 60° C., about 10° C. to about 40° C., or from about 20° C. to about 30° C. In one non-limiting embodiment, the temperature is selected from about 20° C. to about 30° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 7 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • the order of steps prescribed herein can be switched while still reaching the same final product.
  • the oxidation can be carried out in between Step 3 and Step 4, in between Step 4 and Step 5, or in between Step 5 and Step 6;
  • the protection step can be carried out before Step 1, in between Step 3 and Step 4, or in between Step 4 and Step 5;
  • the deprotection step can be carried out in between Step 3 and Step 4, in between Step 4 and Step 5, or after Step 7.
  • the lactam amine is already appropriately protected and Step 2 is not necessary.
  • the reagents and starting materials chosen do not need protection to proceed to the desired product, and Step 2 and Step 6 are not necessary.
  • the lactam amine is a compound of Formula I
  • the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is a compound of Formula II
  • the 5′-hydroxy-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine are compounds of Formula III
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is a compound of Formula IV.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is a spirocycle, for example, 2′-(methylsulfonyl)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one.
  • Step 1 a 4-halo-2-(alkylthio)pyrimidine-5-carbaldehyde is reacted with a lactam amine in a nucleophilic substitution reaction to afford a 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde.
  • the 4-halo-2-(alkylthio)pyrimidine-5-carbaldehyde and lactam amine are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in along with a base that will facilitate the nucleophilic substitution reaction. Any molar ratio of the two reactants can be used that achieves the desired results.
  • a small molar excess of the lactam amine is useful, for example about 1.1 equiv. of lactam amine to about 1.0 equiv. of carbaldehyde.
  • the reaction can be carried out at any temperature that allows the reaction to take place. It has been found that the reaction can be facilitated with heat, including up to reflux. The reaction is allowed sufficient time to provide the desired yield, after which the batch is optionally cooled and purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde.
  • the 4-halo-2-(alkylthio)pyrimidine-5-carbaldehyde is 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde
  • the lactam amine is a spirolactam
  • the base is DIPEA
  • the solvent is tert-butanol
  • the temperature is about 85° C.
  • the time is about 24 hours.
  • the base used in Step 1 can be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, or Trizma.
  • DIPEA
  • the solvent used in Step 1 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DMAc, tert-butanol, DMAP, and DMSO.
  • a mixture of solvents is used in Step 1.
  • the solvent used in Step 1 is dioxane.
  • the solvent is selected from DCM, EtOAc, ethanol, dioxane, tert-butyl alcohol, and THF.
  • the temperature used in Step 1 in non-limiting examples can be from about 50° C. to about 150° C., about 60° C. to about 125° C., about 70° C. to about 110° C., about 80° C. to about 100° C., or from about 90° C. to about 100° C.
  • the temperature is selected from about 80° C. to about 100° C.
  • the reaction temperature is higher than the solvent reflux by use of a reaction vessel that can maintain elevated pressures. Alternatively, while less typical, the reaction can be carried out at room temperature or below.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 1 for about 1 to about 65 hours, about 7 to about 55 hours, about 12 to about 45 hours, about 17 to about 35 hours, or about 22 to about 25 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield.
  • Step 2 a 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is reacted with a protecting group reagent to afford a protected 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde.
  • the 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde and protecting group reagent are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in along with a base that will facilitate the installation of the protecting group. Any molar ratio of the two reactants can be used that achieves the desired results. Typically, a large molar excess of the protecting group reagent is useful, for example about 7 equiv.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a protected 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde.
  • the 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is 2-(methylthio)-4-(3-oxo-1,4-diazaspiro[5.5]undecan-1-yl)pyrimidine-5-carbaldehyde
  • the protecting group reagent is Boc-anhydride
  • the base is DMAP
  • the solvent is dichloromethane
  • the temperature is about 25° C.
  • the time is about 3 hours.
  • the initial lactam amine used was already protected.
  • the lactam substituted pyrimidine reacts appropriately without needing a protecting group.
  • the protecting group reagent used in Step 2 can be any suitable reagent that allows installation of any suitable protecting group, including but not limited to Boc-anhydride, Boc-Cl, CBz-Cl, methyl chloroformate, benzyl chloride, benzoyl chloride, allylic chloride, triflic anhydride, Tf-Cl, tosyl anhydride, and Ts-Cl.
  • the protecting group is Boc and the suitable reagent is either Boc-anhydride or Boc-Cl.
  • the protecting group is CBz and the suitable reagent is CBz-Cl.
  • the base used in Step 2 can be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, and Trizma.
  • DIPEA
  • the solvent used in Step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, water, and THF.
  • a mixture of solvents is used in Step 2.
  • the temperature used in Step 2 in non-limiting examples can be from about ⁇ 20° C. to about 100° C., about ⁇ 10° C. to about 80° C., about 0° C. to about 60° C., about 10° C. to about 40° C., or from about 20° C. to about 30° C. In one non-limiting embodiment, the temperature is selected from about 20° C. to about 30° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 2 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 4 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 3 an optionally protected 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is reacted with a base in a intramolecular cyclization to afford a 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde and base are mixed in a suitable solvent, typically a neutral organic solvent that both the reactant and reagent dissolve in. Any molar ratio of the reactant and reagent can be used that achieves the desired results.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the protected 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is tert-butyl 2′-(methylthio)-6′-oxo-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-7′(8′H)-carboxylate, the base is tBuOK, the solvent is THF, the temperature is about 5° C., and the time is about 2 hours.
  • the base used in Step 3 can be any suitable base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, K
  • the solvent used in Step 3 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, water, and THF.
  • a mixture of solvents is used in Step 3.
  • the temperature used in Step 3 in non-limiting examples can be from about ⁇ 50° C. to about 50° C., about ⁇ 35° C. to about 40° C., about ⁇ 10° C. to about 30° C., about ⁇ 5° C. to about 20° C., or from about 0° C. to about 10° C. In one non-limiting embodiment, the temperature is selected from about 0° C. to about 10° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 3 for about 0.1 to about 20 hours, for about 0.5 to about 15 hours, in about 1 to about 10 hours, in about 1.5 to about 5 hours, or in about 2 to about 3 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 4 Optional Deprotection of 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine
  • Step 4 a 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is deprotected to afford a deprotected 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the protected 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and deprotecting reagent are mixed in a suitable solvent, typically an organic solvent that both reactants dissolve in. Any molar ratio of the reactant and deprotecting reagent can be used that achieves the desired results. Typically a large molar excess of the deprotecting reagent is useful, for example about 5 equiv.
  • deprotecting reagent to about 1.0 equiv. of 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a deprotected 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the protected 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is tert-butyl 2′-(methylthio)-6′-oxo-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidine]-7′(8′H)-carboxylate
  • the deprotecting reagent is hydrochloric acid
  • the solvent is water
  • the temperature is about 25° C.
  • the time is about 2 hours.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine was already unprotected because it was suitable for the prior reactions in the absence of a protecting group.
  • the protecting group is left on to be removed at a later step.
  • the deprotecting reagent used in Step 4 can be any suitable reagent that allows deprotection of any suitable protecting group, including but not limited to TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, formic acid, lactic acid, malic acid, malonic acid, methane sulfonic acid, oxalic acid, phthalic acid, salicyclic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, periodic acid, phosphinic acid, phosphoric acid, palladium on carbon with or without hydrogen gas, platinum on carbon with our without hydrogen gas, triethylsilane
  • the solvent used in Step 4 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, and water.
  • a mixture of solvents is used in Step 4.
  • the deprotecting reagent is selected from DCM, dioxane
  • the temperature used in Step 4 in non-limiting examples can be from about ⁇ 20° C. to about 100° C., about ⁇ 10° C. to about 80° C., about 0° C. to about 60° C., about 10° C. to about 40° C., or from about 20° C. to about 30° C. In one non-limiting embodiment, the temperature is selected from about 20° C. to about 30° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 4 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 5 Optional Oxidation of 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine
  • Step 5 a 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is reacted with an oxidant to afford a 2′-(alkylsulfonyl)-lactam-pyrrolo[2,3-d]pyrimidine or 2′-(alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and oxidant are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in. Any molar ratio of the reactant and oxidant can be used that achieves the desired results.
  • a large molar excess of the oxidant is useful, for example about 5 equiv. of oxidant to about 1.0 equiv. of 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford either a 2′-(alkylsulfonyl)-lactam-pyrrolo[2,3-d]pyrimidine or 2′-(alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidine.
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is 2′-(methylthio)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one
  • the oxidant is oxone
  • the solvent is a mixture of water and acetonitrile
  • the temperature is about 25° C.
  • the time is about 2 hours.
  • the oxidant used in Step 5 can be any suitable reagent that allows oxidation to either the sulfone or sulfoxide oxidation state, including but not limited to oxone, hydrogen peroxide, mCPBA, sodium hypochlorite, and sodium chlorite.
  • the product is a sulfone and the oxidant is oxone.
  • the solvent used in Step 5 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from ACN, water, and dioxane.
  • a mixture of solvents is used in Step 5, for example, water and ACN.
  • the temperature used in Step 5 in non-limiting examples can be from about ⁇ 20° C. to about 100° C., about ⁇ 10° C. to about 80° C., about 0° C. to about 60° C., about 10° C. to about 40° C., or from about 20° C. to about 30° C. In one non-limiting embodiment, the temperature is selected from about 20° C. to about 30° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 5 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • the lactam amine is already appropriately protected and Step 2 is not necessary.
  • the reagents and starting materials chosen do not need protection to proceed to the desired product, and Step 2 and Step 4 are not necessary.
  • the lactam amine is a compound of Formula I
  • the 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is a compound of Formula II
  • the 2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is a compound of Formula IV.
  • 1,4-diazaspiro[5.5]undecan-3-ones can be prepared from cyclohexanones.
  • the 1,4-diazaspiro[5.5]undecan-3-one is initially unprotected and optionally protected during later synthetic steps.
  • Step 1 an appropriately substituted alkyl glycinate or salt thereof is reacted with a cyclohexanone in the presence of TMSCN to afford an alkyl (1-cyanocyclohexyl)glycinate.
  • Cyclohexanone and alkyl glycinate are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in along with a base that will facilitate the reaction.
  • TMSCN is then added slowly to the mixture. Any molar ratio of the two reactants can be used that achieves the desired results.
  • the reaction can be carried out at any temperature that allows the reaction to take place. Due to the exothermic nature of the reaction the temperature is controlled on large scale.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford an alkyl (1-cyanocyclohexyl)glycinate.
  • the alkyl glycinate is methyl glycinate or a salt thereof
  • the base is TEA
  • the solvent is DCM
  • the temperature is about 35° C. or less
  • the time is about 4 hours.
  • the base used in Step 1 can be any suitable base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, K
  • the solvent used in Step 1 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from TEA, ACN, DCM, and DMSO.
  • a mixture of solvents is used in Step 1.
  • the solvent used in Step 1 is dioxane.
  • the solvent is selected from DCM, EtOAc, ethanol, dioxane, tert-butyl alcohol, and THF.
  • the temperature used in Step 1 in non-limiting examples can be from about ⁇ 20° C. to about 50° C., about ⁇ 10° C. to about 40° C., about 0° C. to about 35° C., or about 10° C. to about 30° C. In one non-limiting embodiment, the temperature is selected from about 10° C. to about 30° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product. It should be understood by those of skill in the art that the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield.
  • Step 2 an alkyl (1-cyanocyclohexyl)glycinate or salt thereof is reduced by a hydride source and suitable catalyst, and subsequently undergoes an intramolecular cyclization to afford a 4-diazaspiro[5.5]undecan-3-one.
  • the alkyl (1-cyanocyclohexyl)glycinate is dissolved in a suitable solvent.
  • a reductant is added optionally in the presence of a catalyst to afford reduction of the cyano group to an amine.
  • the amine then acts as a nucleophile in a subsequent intramolecular cyclization to afford a 4-diazaspiro[5.5]undecan-3-one.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 4-diazaspiro[5.5]undecan-3-one.
  • the alkyl (1-cyanocyclohexyl)glycinate is methyl (1-cyanocyclohexyl)glycinate or a salt thereof
  • the solvent is MeOH
  • the hydride source is hydrogen gas
  • the catalyst is platinum oxide
  • the temperature is about 40° C.
  • the time is about 3 hours.
  • the hydride source used in Step 2 can be any suitable hydride source, including but not limited to sodium triacetoxyborohydride, hydrogen gas, sodium borohydride, cyanoborohydride, and ammonia formate.
  • the hydride source is used stoichiometrically with no catalyst, for example sodium triacetoxyborohydride without platinum on carbon.
  • the solvent used in Step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from methanol, water, and ethanol.
  • a mixture of solvents is used in Step 2.
  • the temperature used in Step 2 in non-limiting examples can be from about ⁇ 10° C. to about 90° C., about 0° C. to about 80° C., about 10° C. to about 70° C., about 20° C. to about 60° C., or from about 30° C. to about 50° C. In one non-limiting embodiment, the temperature is selected from about 30° C. to about 50° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 2 in about 0.1 to about 20 hours, in about 0.5 to about 15 hours, in about 1 to about 10 hours, in about 1.5 to about 5 hours, or in about 2 to about 3 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • 1,4-diazaspiro[5.5]undecan-3-ones can be prepared from alkyl 2-oxoacetate and 1-(aminomethyl)cyclohexan-1-amine which may be optionally protected.
  • the 1,4-diazaspiro[5.5]undecan-3-one is a protected, for example, tert-butyl 3-oxo-1,4-diazaspiro[5.5]undecane-4-carboxylate.
  • Step 1 a 1-(aminomethyl)cyclohexan-1-amine is reacted with an alkyl 2-oxoacetate in a reductive amination reaction to afford an alkyl (1-(aminomethyl)cyclohexyl)glycinate.
  • the 1-(aminomethyl)cyclohexan-1-amine and alkyl 2-oxoacetate are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in along with a catalyst and hydride source that will facilitate the reductive amination reaction. Any molar ratio of the two reactants can be used that achieves the desired results.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford an alkyl (1-(aminomethyl)cyclohexyl)glycinate.
  • the 1-(aminomethyl)cyclohexan-1-amine is tert-butyl ((1-aminocyclohexyl)methyl)carbamate
  • the alkyl 2-oxoacetate is ethyl 2-oxoacetate
  • the catalyst is platinum on carbon
  • the hydride source is hydrogen gas
  • the solvent is DCM
  • the temperature is about 25° C.
  • the time is about 24 hours.
  • the hydride source used in Step 1 can be any suitable hydride source, including but not limited to sodium triacetoxyborohydride, hydrogen gas, sodium borohydride, cyanoborohydride, and ammonia formate.
  • the hydride source is used stoichiometrically with no catalyst, for example sodium triacetoxyborohydride without platinum on carbon.
  • the solvent used in Step 1 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • suitable organic solvent including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzen
  • the solvent is selected from DCM, EtOAc, ethanol, tert-butyl alcohol and THF. In an alternative embodiment, a mixture of solvents is used in Step 1.
  • the solvent used in Step 1 is dioxane.
  • the solvent is selected from DCM, EtOAc, ethanol, dioxane, tert-butyl alcohol, and THF.
  • the temperature used in Step 1 in non-limiting examples can be from about ⁇ 50° C. to about 50° C., about ⁇ 35 to about 40° C., about ⁇ 10° C. to about 30° C., about ⁇ 5° C. to about 20° C., or from about 0° C. to about 10° C. In one non-limiting embodiment, the temperature is selected from about 0° C. to about 10° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 1 in about 0.1 to about 20 hours, in about 0.5 to about 15 hours, in about 1 to about 10 hours, in about 1.5 to about 5 hours, or in about 2 to about 3 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 2 an alkyl (1-(aminomethyl)cyclohexyl)glycinate is deprotected to afford a deprotected alkyl (1-(aminomethyl)cyclohexyl)glycinate.
  • the alkyl (1-(aminomethyl)cyclohexyl)glycinate and deprotecting reagent are mixed in a suitable solvent, typically a solvent that both reactants dissolve in. Any molar ratio of the reactant and deprotecting reagent can be used that achieves the desired results. Typically a large molar excess of the deprotecting reagent is useful, for example about 5 equiv. of deprotecting reagent to about 1.0 equiv.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a deprotected alkyl (1-(aminomethyl)cyclohexyl)glycinate.
  • the protected alkyl (1-(aminomethyl)cyclohexyl)glycinate is ethyl (1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)glycinate
  • the deprotecting reagent is hydrochloric acid
  • the solvent is water
  • the temperature is about 25° C.
  • the time is about 2 hours.
  • the alkyl (1-(aminomethyl)cyclohexyl)glycinate was already deprotected because it was suitable for the prior reaction in the absence of a protecting group.
  • the protecting group is left on to be removed at a later step.
  • the deprotecting reagent used in Step 2 can be any suitable reagent that allows deprotection of any suitable protecting group, including but not limited to TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, formic acid, lactic acid, malic acid, malonic acid, methane sulfonic acid, oxalic acid, phthalic acid, salicyclic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, periodic acid, phosphinic acid, phosphoric acid, palladium on carbon with or without hydrogen gas, platinum on carbon with our without hydrogen gas, triethylsilane
  • the solvent used in Step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, and water.
  • a mixture of solvents is used in Step 2.
  • the deprotecting reagent is selected from DCM, dioxane
  • the temperature used in Step 2 in non-limiting examples can be from about ⁇ 20° C. to about 100° C., about ⁇ 10° C. to about 80° C., about 0° C. to about 60° C., about 10° C. to about 40° C., or from about 20° C. to about 30° C. In one non-limiting embodiment, the temperature is selected from about 20° C. to about 30° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 2 in about 1 to about 40 hours, in about 3 to about 35 hours, in about 5 to about 30 hours, in about 10 to about 25 hours, or in about 13 to about 20 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 3 an alkyl (1-(aminomethyl)cyclohexyl)glycinate is reacted with a base in a intramolecular cyclization to afford a 4-diazaspiro[5.5]undecan-3-ones.
  • the alkyl (1-(aminomethyl)cyclohexyl)glycinate and base are mixed in a suitable solvent, typically a neutral organic solvent that both the reactant and reagent dissolve in. Any molar ratio of the reactant and reagent can be used that achieves the desired results.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 4-diazaspiro[5.5]undecan-3-one.
  • the alkyl (1-(aminomethyl)cyclohexyl)glycinate is ethyl (1-(aminomethyl)cyclohexyl)glycinate
  • the solvent is THF
  • the temperature is about 5° C.
  • the time is about 2 hours.
  • the base used in Step 3 can be any suitable base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, K
  • the solvent used in Step 3 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, water, and THF.
  • a mixture of solvents is used in Step 3.
  • the temperature used in Step 3 in non-limiting examples can be from about ⁇ 50° C. to about 50° C., about ⁇ 35 to about 40° C., about ⁇ 10° C. to about 30° C., about ⁇ 5° C. to about 20° C., or from about 0° C. to about 10° C. In one non-limiting embodiment, the temperature is selected from about 0° C. to about 10° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 3 in about 0.1 to about 20 hours, in about 0.5 to about 15 hours, in about 1 to about 10 hours, in about 1.5 to about 5 hours, or in about 2 to about 3 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • 1,4-diazaspiro[5.5]undecan-3-ones can be prepared from cyclohexanone utilizing a cyano intermediate.
  • Step 1 a cyclic ketone is reacted with a source of cyanide and ammonia and optionally additional reagents or catalysts to afford a 1-aminocycloalkyl-1-carbonitrile.
  • the cyclic ketone, cyanide source, and ammonia source are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in. Any molar ratio of the two reactants can be used that achieves the desired results.
  • the reaction can be carried out at any temperature that allows the reaction to take place. The reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 1-aminocycloalkyl-1-carbonitrile.
  • the cyclic ketone is cyclohexanone
  • the cyanide source is TMSCN
  • the ammonia source is ammonia
  • 1-aminocycloalkyl-1-carbonitrile is 1-(aminomethyl)cyclohexan-1-amine
  • the catalyst is titanium isopropoxide.
  • centrifugation is used in the isolation of the 1-aminocyclalkyl-1-carbonitrile.
  • Celite filtration is used in the isolation of the 1-aminocyclalkyl-1-carbonitrile.
  • the solvent used in Step 1 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, EtOAc, ethanol, tert-butyl alcohol and THF.
  • a mixture of solvents is used. In one embodiment no solvent
  • the solvent used in Step 1 is dioxane.
  • the solvent is selected from DCM, EtOAc, ethanol, dioxane, tert-butyl alcohol, and THF.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 1 in about 0.1 to about 20 hours, in about 0.5 to about 15 hours, in about 1 to about 10 hours, in about 1.5 to about 5 hours, or in about 2 to about 3 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • 1-aminocycloalkyl-1-carbonitrile is reduced to afford a 1-(aminomethyl)cycloalkyl-1-amine.
  • the 1-aminocycloalkyl-1-carbonitrile and a reducing reagent are mixed in a suitable solvent, typically a solvent that both reactants dissolve in. Any molar ratio of the reactant and reducing reagent can be used that achieves the desired results. Typically a molar excess of the reducing reagent is useful, for example about 2 equiv. of reducing reagent to about 1.0 equiv. of 1-aminocycloalkyl-1-carbonitrile.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford 1-(aminomethyl)cycloalkyl-1-amine.
  • the 1-aminocycloalkyl-1-carbonitrile is 1-(aminomethyl)cyclohexan-1-amine
  • the reducing reagent is lithium aluminium hydride (LAH)
  • the temperature is about 45° C.
  • the time is about 30 minutes.
  • the reducing reagent used in Step 2 can be any suitable reagent that allows reduction of the cyano group, including but not limited to LAH, BH 3 -THF, BH 3 SMe 2 , H 2 , H 2 with Raney Nickel, and H 2 with Pd/C.
  • the solvent used in Step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, and water.
  • a mixture of solvents is used in Step 2.
  • the temperature used in Step 2 in non-limiting examples can be from about ⁇ 20° C. to about 100° C., about ⁇ 10° C. to about 90° C., about 0° C. to about 80° C., about 10° C. to about 70° C., or from about 20° C. to about 60° C. In one non-limiting embodiment, the temperature is selected from about 30° C. to about 50° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 2 in about 10 minutes to about 3 hours, in about 10 minutes to about 2 hours, in about 10 minutes to about 1 hour, in about 10 to about 50 minutes, or in about 20 to about 40 minutes.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 3 a 1-(aminomethyl)cycloalkyl-1-amine is reacted with a protecting group reagent afford a protected 1-(aminomethyl)cycloalkyl-1-amine.
  • the 1-(aminomethyl)cycloalkyl-1-amine and protecting group reagent are mixed in a suitable solvent, typically a neutral organic solvent that both reactants dissolve in along with a base that will facilitate the installation of the protecting group. Any molar ratio of the two reactants can be used that achieves the desired results.
  • a molar deficiency or equivalence of the protecting group reagent is useful, for example about 0.6, 0.7, 0.8, 0.9, 1, or 1.1 equiv.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a protected 1-(aminomethyl)cycloalkyl-1-amine.
  • the 1-(aminomethyl)cycloalkyl-1-amine is 1-(aminomethyl)cyclohexan-1-amine
  • the protecting group reagent is Boc-anhydride
  • the protected 1-(aminomethyl)cycloalkyl-1-amine is tert-butyl ((1-aminocyclohexyl)methyl)carbamate
  • no base is used
  • the temperature is about-70° C.
  • the protecting group reagent used in Step 3 can be any suitable reagent that allows installation of any suitable protecting group, including but not limited to Boc-anhydride, Boc-Cl, CBz-Cl, methyl chloroformate, benzyl chloride, benzoyl chloride, allylic chloride, triflic anhydride, Tf-Cl, tosyl anhydride, and Ts-Cl.
  • the protecting group is Boc and the suitable reagent is either Boc-anhydride or Boc-Cl.
  • the protecting group is CBz and the suitable reagent is CBz-Cl.
  • Step 3 is conducted without the addition of a base.
  • the base can be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine
  • the solvent used in Step 3 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, dioxane, water, and THF.
  • a mixture of solvents is used in Step 3.
  • the temperature used in Step 3 in non-limiting examples can be from about ⁇ 100° C. to about 20° C., about ⁇ 90° C. to about 0° C., about ⁇ 80° C. to about ⁇ 10° C., about ⁇ 80° C. to about ⁇ 40° C., or from about ⁇ 80° C. to about ⁇ 60° C. In one non-limiting embodiment, the temperature is selected from about ⁇ 80° C. to about ⁇ 60° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 3 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 4 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 4 a protected 1-(aminomethyl)cycloalkyl-1-amine is reacted with a base, and alkyl 2-bromoacetate to afford an alkyl (1-(((protecting group)amino)methyl)cycloalkyl)glycinate.
  • the protected 1-(aminomethyl)cycloalkyl-1-amine and base are mixed in a suitable solvent, typically a neutral organic solvent that both the reactant and reagent dissolve in. Any molar ratio of the reactant and reagent can be used that achieves the desired results.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford an alkyl (1-(((protecting group)amino)methyl)cycloalkyl)glycinate.
  • the protected 1-(aminomethyl)cycloalkyl-1-amine is tert-butyl ((1-aminocyclohexyl)methyl)carbamate
  • the solvent is acetonitrile
  • the base is K 2 CO 3
  • the alkyl (1-(((protecting group)amino)methyl)cycloalkyl)glycinate is methyl (1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)glycinate.
  • the base used in Step 4 can be any suitable base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, Proton-sponge, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, K
  • the solvent used in Step 4 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from acetonitrile, dioxane, water, and THF.
  • a mixture of solvents is used in Step 4.
  • the temperature used in Step 3 in non-limiting examples can be from about 0° C. to about 100° C., about 0 to about 90° C., about 0° C. to about 80° C., about 20° C. to about 80° C., or from about 30° C. to about 80° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 4 in about 0.1 to about 20 hours, in about 0.5 to about 15 hours, in about 1 to about 10 hours, in about 1.5 to about 5 hours, or in about 2 to about 3 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • Step 5 an alkyl (1-(((protecting group)amino)methyl)cycloalkyl)glycinate is deprotected with a deprotecting reagent and then treated with an acid to cause an intramolecular cyclization to afford a 4-diazaspiro[5.5]undecan-3-one.
  • the alkyl (1-(((protecting group)amino)methyl)cycloalkyl)glycinate and deprotecting reagent are mixed in a suitable solvent, typically a solvent that both the reactant and reagent dissolve in. Any molar ratio of the reactant and reagent can be used that achieves the desired results.
  • the reaction can be carried out at any temperature that allows the reaction to take place.
  • the reaction is allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable means, including filtration, crystallization, and column chromatography, to afford a 4-diazaspiro[5.5]undecan-3-one.
  • the alkyl (1-(((protecting group)amino)methyl)cycloalkyl)glycinate is methyl (1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)glycinate, the solvent is DCE, the acid is TFA, the deprotecting agent is TFA, the temperature is about reflux, and the 4-diazaspiro[5.5]undecan-3-one is 1,4-diazaspiro[5.5]undecan-3-one.
  • the deprotecting reagent used in Step 5 can be any suitable reagent that allows deprotection of any suitable protecting group, including but not limited to TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, formic acid, lactic acid, malic acid, malonic acid, methane sulfonic acid, oxalic acid, phthalic acid, salicyclic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, periodic acid, phosphinic acid, phosphoric acid, palladium on carbon with or without hydrogen gas, platinum on carbon with our without hydrogen gas, triethylsilane
  • the acid used in Step 5 can be any suitable acid that allows intramolecular cyclization, including but not limited to TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, formic acid, lactic acid, malic acid, malonic acid, methane sulfonic acid, oxalic acid, phthalic acid, salicyclic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, periodic acid, phosphinic acid, and phosphoric acid.
  • the acid is TFA.
  • the solvent used in Step 5 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
  • the solvent is selected from DCM, DCE, TFA, and THF.
  • a mixture of solvents is used in Step 5.
  • the temperature used in Step 5 in non-limiting examples can be from about 30° C. to about 100° C., about 35 to about 90° C., about 50° C. to about 85° C., about 55° C. to about 85° C., or from about 60° C. to about 85° C.
  • the reaction can be allowed to proceed for a sufficient time to obtain the desired yield of product.
  • the reaction may proceed in Step 5 in about 0.1 to about 20 hours, in about 0.5 to about 15 hours, in about 1 to about 10 hours, in about 1.5 to about 5 hours, or in about 2 to about 3 hours.
  • the time and temperature of the reaction are related. For example if a higher temperature is used a lower reaction time may obtain the desired yield. Alternatively if a lower temperature is used a higher reaction time will be necessary to obtain the desired yield, but fewer byproducts may be present.
  • the 4-diazaspiro[5.5]undecan-3-one is isolated as a salt. In another embodiment, the 4-diazaspiro[5.5]undecan-3-one is isolated as a free-base.
  • the 4-diazaspiro[5.5]undecan-3-one salt is dissolved or suspended in a solvent and is then subjected to a base.
  • the solvent is ethanol.
  • the solvent is DCM.
  • the base is K 2 CO 3 .
  • the solvent is ethanol and the base is K 2 CO 3 .
  • the solvent is DCM and the base is K 2 CO 3 .
  • a number of the compounds used in the process of preparation described herein are new. Some of these are described below.
  • Formula II is a heteroaryl bonded to a spirocyclic lactam.
  • Non-limiting examples of compounds falling within Formula II are illustrated below. This disclosure includes all combinations of these definitions so long as a stable compound results.
  • this disclosure includes compounds and salts of Formula IIA:
  • R 5 is as defined herein.
  • Non-limiting examples of R 5 are hydrogen, bromine, chlorine, fluorine, iodine, —CF 3 , —OEt, —OMe, —NCH 3 OMe, and —OC(O)CH 3
  • this disclosure includes compounds and salts of Formula IIB:
  • R 2 is as defined herein.
  • Non-limiting examples of R 2 are hydrogen, -Boc, -CBz, -Bn, methyl carbamate, and methyl.
  • this disclosure includes compounds and salts of Formula IIC:
  • R 1 is as defined herein.
  • Non-limiting examples of R 1 are methyl, —CF 3 , -Bn, -Ph, -Et, propyl, and isopropyl.
  • this disclosure includes compounds and salts of Formula IID:
  • R 1 is as defined herein.
  • Non-limiting examples of R 1 are methyl, —CF 3 , -Bn, -Ph, -Et, propyl, and isopropyl.
  • Non-limiting examples of compounds that can be synthesized by the processes presented in the present invention include:
  • the compounds of the above Formulas are used in the synthesis of CDK inhibitors.
  • Scheme 1-1 Starting from an appropriately substituted halo pyrimidine, compounds of the present invention can be prepared.
  • Step 1 the appropriately substituted halo pyrimidine is subjected to 1,4-diazaspiro[5.5]undecan-3-one in the presence of base and heat to afford a substituted spirolactam.
  • Step 2 the appropriately substituted spirolactam is protected with a group selected from R 2 .
  • Step 3 the protected spirolactam is cyclized in the presence of base to afford a fused spirolactam.
  • the fused spirolactam can be optionally oxidized to a sulfoxide or sulfone after Step 3, Step 4, Step 5, or Step 6.
  • Step 4 the hydroxyl group of the fused spirolactam is converted to a leaving group.
  • Step 5 the leaving group is dehydrated to afford a compound of Formula IV.
  • Step 6 the compound of Formula IV is optionally deprotected.
  • Step 1 the appropriately substituted halo pyrimidine is subjected to 1,4-diazaspiro[5.5]undecan-3-one in the presence of base and heat to afford a substituted spirolactam.
  • Step 2 the appropriately substituted spirolactam is protected with a group selected from R 2 .
  • Step 3 the protected spirolactam is cyclized in the presence of base to afford a fused spirolactam of Formula IV.
  • the fused spirolactam can be optionally oxidized to a sulfoxide or sulfone after Step 3 or Step 4. Oxidation prior to Step 3 results in undesired byproducts.
  • Step 4 the compound of Formula IV is optionally deprotected.
  • Scheme 1-3 Starting from an appropriately substituted alkyl glycinate, compounds of the present invention can be prepared.
  • Step 1 the appropriately substituted alkyl glycinate is subjected to cyclohexanone and TMSCN in the presence of base to afford a cyano species.
  • Step 2 the appropriately substituted cyanospecies is reduced and subsequently cyclized to afford a compound of Formula I.
  • Scheme 1-4 Starting from an appropriately substituted 1-(aminomethyl)cyclohexan-1-amine, compounds of the present invention can be prepared.
  • Step 1 the appropriately substituted 1-(aminomethyl)cyclohexan-1-amine is reductively aminated with an aldehyde.
  • Step 2 the appropriately substituted cyclohexane amine is optionally deprotected (i.e.: the group selected from R 2 if not H is optionally replaced by H).
  • Step 3 the cyclohexane amine is cyclized to afford a compound of Formula I.
  • Step 4 the compound of Formula I is optionally protected.
  • Step 1 the appropriately substituted halo pyrimidine is subjected to 1,4-diazaspiro[5.5]undecan-3-one in the presence of base and heat to afford a substituted spirolactam.
  • Step 2 the protected spirolactam is cyclized in the presence of base to afford a fused spirolactam.
  • the fused spirolactam can be optionally oxidized to a sulfoxide or sulfone after Step 2, Step 3, Step 4, or Step 5. Oxidation prior to Step 2 results in undesired byproducts.
  • Step 3 the hydroxyl group of the fused spirolactam is converted to a leaving group.
  • Step 4 the leaving group is dehydrated to afford a compound of Formula IV.
  • Step 5 the compound of Formula IV is optionally deprotected.
  • Step 1 the appropriately substituted halo pyrimidine is subjected to 1,4-diazaspiro[5.5]undecan-3-one in the presence of base and heat to afford a substituted spirolactam.
  • Step 2 the protected spirolactam is cyclized in the presence of base to afford a fused spirolactam of Formula IV.
  • the fused spirolactam can be optionally oxidized to a sulfoxide or sulfone after Step 2 or Step 3. Oxidation prior to Step 2 results in undesired byproducts.
  • Step 3 the compound of Formula IV is optionally deprotected.
  • Scheme 1-7 Starting from compound of Formula IV a CDK4/6 inhibitor can be prepared.
  • a heteroaryl amine is subjected to a base and a compound of Formula IV is added slowly under chilled conditions to afford a nucleophilic substitution reaction.
  • the compound of Formula IV can previously be prepared as described in the schemes herein.
  • the first step in the ester route is a SNAr nucleophilic substitution of Cl group in commercially available ester 3 using spirolactam 4. Due to low reactivity of 4, a reaction temperature of 85-95° C. was required. Because of the temperature requirements, DIPEA and dimethylacetamide were selected as the base and solvent, respectively. The reaction follows second-order kinetics and usually stalls after ⁇ 85% conversion. Therefore, the reaction was typically stopped after 60 hours by first cooling it to room temperature at which point solid formation was observed. The mixture was then partitioned between MTBE and water and product was filtered with excellent purity with ⁇ 53% yield of the desired product 5. The obtained compound 5 was protected with a Boc group using Boc anhydride and DMAP as the catalyst and dichloromethane as the solvent.
  • the intermediate 6 was obtained in a quantitative yield. Due to the semi-solid nature of compound 6, the material was taken to the next step without further purification.
  • the Dieckmann condensation was initially performed with strong bases such as LiHMDS and tBuOK.
  • a similar result to the aldehyde route (Scheme 2-2) was obtained: a partial deprotection of Boc group was observed that required column chromatography. However, the best results were obtained when DBU was used as base and THF as solvent.
  • the reaction outcome was complete, clean conversion of 6 to 7. Moreover, the product crystallized from the reaction mixture upon seeding, and a quantitative yield was obtained for the two steps.
  • the hydroxyl group of 7 was removed via a two-step procedure.
  • compound 7 was converted completely into triflate 8 using triflic anhydride and triethylamine in dichloromethane.
  • the reaction was found to proceed well at 0° C. Due to the potential instability of the triflate intermediate, it was not isolated. It was immediately taken to the next step and reduced with triethylsilane and palladium tetrakis to afford the product 9 after ethyl acetate crystallization in ⁇ 70% yield.
  • the Boc group of 9 was removed using trifluoroacetic acid in dichloromethane to afford 10.
  • Intermediate 10 was converted into the final sulfone 11 using OxoneTM in acetonitrile/water solvent system.
  • the obtained sulfone 11 was use-tested in the coupling step and was found to perform well.
  • the route to sulfone 11 was developed which eliminated the use of column chromatography with good to excellent yields on all steps.
  • Scheme 2-2 The first step of Scheme 2-2 consistently afforded product 13 contaminated with one major impurity found in substantial amount. Thorough evaluation of the reaction impurity profile by LC-MS and 2D NMR was performed, which showed the impurity was structurally the condensation of two aldehyde 12 molecules and one molecule of lactam 4. Therefore, column chromatography was required to purify compound 13, which consistently resulted in a modest 30% yield. A solvent screen revealed that sec-butanol, amyl alcohol, dioxane, and tert-butanol can all be used in the reaction but a similar conversion was observed in each case. However, tert-butanol provided the cleanest reaction profile, so it was selected as a solvent for the reaction.
  • the second step (Boc protection of the free lactam) proceeded well using DMAP as a catalyst in dichloromethane at room temperature.
  • the product 14 is a thick oil, and, therefore, cannot be purified by crystallization.
  • the Boc protected intermediate 14 was cyclized successfully into the desired pentacyclic structure 10 upon treatment with a strong base such as LiHMDS or tBuOK. Surprisingly, the Boc group was partially removed during the reaction. The level of deprotection was independent from the internal reaction temperature and was positively correlated with excess of base used. Therefore the mixture of the desired product 10 and 10-Boc compound was treated with acid to completely deprotect Boc group.
  • the conversion of methyl sulfide into the final sulfone 11 was carried out with OxoneTM. Initially a mixture of methanol and water was used for the reaction. As the result, a partial displacement of sulfone by methoxy group was detected. The methanol was replaced with acetonitrile and the sulfone
  • Step 2 Starting with cyclohexanone, compounds of the present invention can be prepared.
  • Step 1 the methyl glycinate is subjected to cyclohexanone and TMSCN in the presence of triethyl amine in DCM to afford 15.
  • Step 2 hydrogenated with hydrogen gas in the presence of catalytic platinum oxide and subsequently undergoes an intramolecular cyclization to afford compound 16 which is used in the schemes above.
  • Step 1 compound 17 is subjected to ethyl 2-oxoacetate in the presence platinum on carbon and hydrogen gas to afford compound 18.
  • Step 2 compound 18 is Boc-deprotected with hydrochloric acid.
  • Step 3 compound 18 is cyclized to afford compound 16 which is used in the schemes above.
  • Scheme 2-6 Starting from compound 11 the CDK 4/6 inhibitor 20 can be prepared.
  • Step 1 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine is subjected to LiHMDS and compound 11 is added slowly under chilled conditions to afford a nucleophilic substitution reaction and compound 20.
  • Compound 11 can be prepared as described in the schemes herein.
  • the batch was heated to 90-95° C., and after 60 h, IPC confirmed ⁇ 14% (AUC) of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate remained.
  • the batch was cooled to RT, and precipitate formation was observed.
  • the suspension was diluted with MTBE (100 mL, 2 vol) and water (442 mL, 9 vol) and stirred for 2 h at RT.
  • the product was isolated by vacuum filtration and washed with MTBE (49 mL, 1 vol).
  • the batch was seeded with the product (1.0 g) and was cooled to 0° C. The slurry was stirred at 0° C. for 2 h. The product was isolated by vacuum filtration and washed with cold (0° C.) THF (50 mL, 1 vol). The solid cake was conditioned for 1 h and dried under vacuum at 40° C. for 16 h to afford 7 [47 g, quantitative yield] as a light orange solid with a purity of >99% AUC. The color of the product changed into yellow once the batch was exposed to air for an extended period of time ( ⁇ 1 day). Material was isolated with substantial amount DBU, according to proton NMR. However, it did not interfere with the next step.
  • the flask was charged with tetrakis(triphenylphosphine)palladium(0) (11.3 g, 0.01 mol, 0.1 equiv.). The batch was heated to 45-50° C., and after 14 h, IPC confirmed no starting material remained. The batch was transferred to a 500 mL, separatory funnel while still warm. The reaction was partitioned between water (5 vol) and ethyl acetate (5 vol). The aqueous layer was extracted with ethyl acetate (3 ⁇ 3 vol). The organic layers were combined and concentrated down to 2 volumes. The precipitate was filtered and washed with ethyl acetate (2 ⁇ 1 vol). The solid cake was conditioned for 1 h and dried under vacuum at 40° C.
  • the batch was transferred to a 500 mL, separatory funnel and washed with saturated sodium bicarbonate (100 mL). The aqueous layer was extracted with ethyl acetate (3 ⁇ 20 vol). The organic layers were combined and concentrated down to 3 volumes and product precipitated. The precipitate was filtered and conditioned for 1 h and dried under vacuum at 40° C. for 16 h to afford 9 [489 mg, quantitative yield] as an off-white solid.
  • the crude 15 was dissolved in IPA (4 L). The solution was treated with HCl/IPA solution (4.4 mol/L, 1.1 L) at RT. A large amount of solid was precipitated during the addition. The resulting suspension was stirred for 2 hrs. The solid product was collected by vacuum filtration and rinsed with MTBE (800 mL). 819 g of pure 15 was obtained as a white solid. The yield was 88.4%.
  • the sulfone 1000 g; 1.00 mol was added in five additions. The reaction proceeded until HPLC analysis of an IPC sample indicated less than 1% of sulfone 11 remained. After completion of the reaction, ammonium chloride was added to the reaction mixture. The mixture stirred at ⁇ 32° C. for at least 30 minutes and the solids collected by filtration to afford 20 (900 g, 99.1% purity, 64.2% yield).
  • the spirolactam is made via the synthetic scheme above.
  • the reaction sequence proceeds in higher yield.
  • the chemistry used in Step 1 is described in the literature ( J. Org. Chem. 2005, 70, 8027-8034), and was performed on a kilogram scale.
  • the chemistry to convert Compound 24 into the spirolactam was also demonstrated on kilogram scale.
  • the Boc protection of Compound 23, is carried out at ⁇ 70° C. in order to limit formation of the di-Boc protected product. Experimental details of a 200 g pilot run are described below.
  • cyclohexanone 21 200 g was converted to 22 using Ti(Oi-Pr) 4 /TMSCN/NH3. After work-up, 213 g of 22 was obtained. The H-NMR was clean. The yield was 84%.
  • the titanium salts were removed by vacuum filtration. In one embodiment, the titanium salts are removed by centrifugation or Celite filtration.
  • Step 5 Step 6
  • Step 7 19 FB 19 Salt Pd ppm 14700 779 164 19 14
  • Step 5 The material after Step 5 was isolated containing 1.47% (14700 ppm) of residual palladium. This data represents the highest level of palladium in the worst case scenario.
  • the workup conditions of the latter steps purged nearly all of the palladium and the final product, 19 bis HCl salt, contained 14 ppm of Pd, which is below the standard 20 ppm guideline. The Pd levels will likely be even lower once the catalyst loading is optimized in Step 5.

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